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Download The 2 alleles on chromosome 13q14 must be inactivated
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1. 2. 3. 4. 5. 6. Self sufficiency in growth factors Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade and metastasize A class of genes that normally suppress cell proliferation. Examples are p53 and Rb. Antigrowth signals can prevent cell proliferation by 2 mechanism: 1-Cause the dividing cell go to Go phase 2-The cell enter post-mitotic differentiated pool & lose replicative potential The molecular level of antigrowth signals exert their effects on G1-S checkpoint of the cell cycle, controlled by Rb gene Mutations that inactivate the tumor suppressor gene products can release cells from growth suppression and lead to hyper proliferation. In 1974 Knudson proposed tow- hits hypothesis Both alleles of the tumor suppressor gene must be inactivated by mutation for hyperproliferation to occur. Cell become malignant if it homozygous for the mutant gene Recessive cancer gene TUMOR SUPPRESSOR GENES RB gene13q14--- 1st TSG discovered Present in every somatic cell in active(hypoph.) & inactive (hyperphosphorelated )form Act as a brake prevent cell from moving from G1S When GF stimulate cell, The cyclin D,E &CDK-phosphorelation of RBinactivation-release the brake. 60% of retinoblastoma (Rb) are sporadic 40% are familial, an autosomal dominant trait The 2 alleles on chromosome 13q14 must be inactivated Heterozygous-----one Rb gene is not mutant no cancer) Homozygous------two Rb genes are mutant =cancer Loss of hrterozygosity of normal Rb gene Seen in > 70 % of human cancers Both alleles has to be mutated Usually mutation is aquired/ Viruses as HepB,EBV,HPV Can be inherited (one allel is mutated) as Li Fraumeni syndrome (25 fold increase risk of ca by age 50) Ataxia telangiectasia-> can not repair x-ray caused DNA damage, ATM protein (damage sensor) is mutated so inactivate TP53 ( TP53 is normal) APC gene loss lead to tumor development, both copies must be lost. Seen in70-80% of sporadic colon ca APC may be normal but B catenin mutated Inherited mutation of one allele will develop 100-1000 of adenomatous polyps in the colon by the age of 10 or 20ys. One or more polyps will develop colon ca by the age of 40ys (Familial Polyposis coli) APC mutation lead to adenoma and more mutation are needed for ca to develop